Alzheimer’s Research UK

There’s something about tau

Shibley Rahman 0 Comments

Tau

Alzheimer’s disease is the most prevalent type of dementia globally, and therefore traditionally gets the most focus. However, there are other neurodegenerative conditions of note which are of massive importance. For example, neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterized by dystonia, parkinsonism and spasticity. Models of Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease and Huntington’s disease show some striking similarities to the corresponding human pathologies in terms of axonal transport disruption, protein aggregation, synapse loss and some behavioural phenotypes (Gilley, Adalbert and Coleman, 2011). In early stages of Alzheimer’s disease, neurofibrillary tangles (NFT) are largely restricted to the entorhinal cortex and medial temporal lobe. At later stages, when clinical symptoms generally occur, NFT involve widespread limbic and association cortices. At this point in the disease, amyloid plaques are also abundantly distributed in the cortex.

Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from adult cells. The iPSC technology was pioneered by Shinya Yamanaka’s lab in Kyoto, Japan, who showed in 2006 that the introduction of four specific genes encoding transcription factors could convert adult cells into pluripotent stem cells. He was awarded the 2012 Nobel Prize along with Sir John Gurdon “for the discovery that mature cells can be reprogrammed to become pluripotent.”

Pluripotent stem cells hold great promise in the field of regenerative medicine. Because they can propagate indefinitely, as well as give rise to every other cell type in the body (such as neurons, heart, pancreatic, and liver cells), they represent a single source of cells that could be used to replace those lost to damage or disease.

According to Wray and Fox (2016),

“It is the use of stem cells as disease models that perhaps has the most to offer in terms of immediate gain, and the most exciting development is the potential to assay potential therapeutics with induced pluripotent stem cells (iPSCs).”

But Wray and Fox (2016) later comment:

“Of particular relevance to Alzheimer’s disease is the fi ending that the expression profile of tau remains feral-like in iPSC-derived neurons until 1 year in culture. Even in cases of familial disease with the earliest onset, the disease only manifests clinically several decades after the onset of pathology and structural changes—how effectively will iPSCs recapitulate the full time course of disease-associated molecular changes?”

Tau proteins (or τ proteins, after the Greek letter by that name) are proteins that stabilise parts of the cell called “microtubules”. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes. Pathologies and dementias of the nervous system such as Alzheimer’s disease are associated with tau proteins that have become defective and no longer stabilise microtubules properly.

The tau hypothesis of Alzheimer’s disease states that excessive or abnormal phosphorylation of tau results in the transformation of normal adult tau into PHF-tau (paired helical filament) and NFTs (neurofibrillary tangles). But it is clearly more complicated than that. Deposition of highly phosphorylated tau in the brain is the most significant neuropathological and biochemical characteristic of the group of neurodegenerative disorders termed the tauopathies. Pathological hyperphosphorylation of the microtubule-associated protein tau is characteristic of Alzheimer’s disease and the associated tauopathies. The reciprocal relationship between phosphorylation and O-GlcNAc modification of tau and reductions in O-GlcNAc levels on tau in AD brain offers motivation for the generation of potent and selective inhibitors that can effectively enhance O-GlcNAc in vertebrate brain (Yuzwa et al., 2008).

The discovery of tau fragments in these diseases suggests that tau cleavage and tau phosphorylation, both of which induce conformational changes in tau, could each have roles in disease pathogenesis. As Hanger and Wray (2010) note, the identities of the proteases responsible for degrading tau, resulting in the appearance of truncated tau species in physiological and pathological conditions, are not known.

The Bavarian psychiatrist Alois Alzheimer is traditionally credited with the first description of the most characteristic pathological brain change—neurofibrillary tangles (NFT)—of a yet-unnamed disease in a 51-year-old woman from Frankfurt am Main, who had developed dementia.

During the 1990s, the significance of tau pathology for neurodegenerative diseases, in particular for dementia of the Alzheimer Type, remained in the shadow of the amyloid based approaches. However, as the distribution pattern and overall quantity of amyloid turned out to be of limited significance for pathological staging of AD progression and symptom severity, and after detailed studies of the maturation and distribution of NFTs showing correlation with degree of cognitive decline and memory impairment in Alzheimer’s disease, Braak and Braak proposed a neuropathological staging of the gradual deposition of abnormal tau within vulnerable neurons in brain areas in the form of either NFT or neuropil threads. Post-mortem Braak staging of neurofibrillary tau tangle topographical distribution is one of the core neuropathological criteria for the diagnosis of Alzheimer’s disease.

Based on the biochemically diverse range of pathological tau proteins, Šimić and colleagues (2006) have recently reviewed a number of different approaches which have been proposed to develop new potential therapeutics. Here we discuss some of the most promising ones: inhibition of tau phosphorylation, proteolysis and aggregation, promotion of intra- and extracellular tau clearance, and stabilization of microtubules.

The recent development of candidate PET imaging tracers targeting aggregated tau (now enables not only the brain burden but also the anatomical distribution of tau pathology to be mapped directly in living subjects. One such PET tracer, 18F-AV-1451 (also known as 18F-T807), has been shown to bind selectively to paired-helical filament (PHF) tau, and to exhibit favourable kinetics, low non-specific binding and differential uptake in Alzheimer’s disease versus healthy control subjects. It has been very recently been reported that in vivo 18F-AV-1451 positron emission tomography images across the Alzheimer’s disease spectrum can be classified into patterns similar to those prescribed by Braak neuropathological staging of tau pathology (Schwarz et al., 2016).

But there’s more to tau than Alzheimer’s disease. In NBIA, iron accumulates in the basal ganglia and may be accompanied by Lewy bodies, axonal swellings and hyperphosphorylated tau depending on NBIA subtype (Arber et al., 2015). And there’s more to Alzheimer’s disease than tau. For example, results from Pooler and colleagues (Pooler et al., 2015) strongly support the hypothesis that cortical amyloid accelerates the spread of tangles throughout the cortex and amplifies tangle-associated neural system failure in AD. The story is gradually though unravelling.

Talk

Dr Selina Wray will be giving a presentation at 4 pm today in session 11 of the Alzheimer’s Research UK Research Conference entitled “Modelling tauopathy in patient-derived neutrons: good things come to those who wait?” (link here).

Recommended reading

Arber CE, Li A, Houlden H, Wray S. Insights into molecular mechanisms of disease in neurodegeneration with brain iron accumulation: unifying theories. Neuropathol Appl Neurobiol. 2015 Apr 14. doi: 10.1111/nan.12242. [Epub ahead of print].

Gilley J, Adalbert R, Coleman MP. Modelling early responses to neurodegenerative mutations in mice. Biochem Soc Trans. 2011 Aug;39(4):933-8. doi: 10.1042/BST0390933.

Hanger DP, Wray S. Tau cleavage and tau aggregation in neurodegenerative disease. Biochem Soc Trans. 2010 Aug;38(4):1016-20. doi: 10.1042/BST0381016.

Schwarz AJ, Yu P, Miller BB, Shcherbinin S, Dickson J, Navitsky M, Joshi AD, Devous MD Sr, Mintun MS Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages. Brain. 2016 Mar 2. pii: aww023. [Epub ahead of print].

Šimić G, Babić Leko M, Wray S, Harrington C, Delalle I, Jovanov-Milošević N, Bažadona D, Buée L, de Silva R, Di Giovanni G, Wischik C, Hof PR. Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies. Biomolecules. 2016 Jan 6;6(1). pii: E6. doi: 10.3390/biom6010006.

Wray S, Fox NC. Stem cell therapy for Alzheimer’s disease: hope or hype? Lancet Neurol. 2015 Dec 15. pii: S1474-4422(15)00382-8. doi: 10.1016/S1474-4422(15)00382-8. [Epub ahead of print].

Yuzwa SA, Macauley MS, Heinonen JE, Shan X, Dennis RJ, He Y, Whitworth GE, Stubbs KA, McEachern EJ, Davies GJ, Vocadlo DJ.29. A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo. Nat Chem Biol. 2008 Aug;4(8):483-90. doi: 10.1038/nchembio.96. Epub 2008 Jun.

It’s the diagnosis and research stupid, but don’t forget about care

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drugs

Anyone linked to the UK government would prefer you not to talk about the crisis in social care. This gets in the way of shimmering spin about current dementia press releases.

But we know that the patient experience of people with dementia and carers is often destroyed by delayed discharges. If your train is late, it’s inappropriate for you to be labelled ‘a platform blocker’. This government, like the previous one, is failing to get on top of this problem.

If you’d believe the grass is greener on the dementia diagnosis front you’d be wrong. People languishing without a formal diagnosis is not right. But if we want high quality prompt diagnoses we should be able to pay for them.

Jeremy Hunt mysteriously views dementia as the ‘jewel in his crown’, but in fact there is a shared ethos between the NHS and English dementia strategy. That is, a stench of the ‘something for nothing’ culture – like paying #juniordoctors to stretch their work to seven days for the same money.

The Dementia Discovery Fund, launched today at the Alzheimer’s Research UK conference in Manchester by Jane Ellison MP, will pay for the development of new drugs for dementia. The announcement is seek to confirm that some of the world’s largest pharmaceutical companies have joined forces to seek new treatments for a group of brain diseases affecting 850,000 people in the UK.

They include Biogen, GlaxoSmithKline, Johnson and Johnson, Lilly, Pfizer and Takeda. The giant firms have signed up with Alzheimer’s Research UK to form a ground-breaking public-private partnership.

This is highly reminiscent of the approach which was taken for the development of drugs for HIV. Some time ago, ater spending a few years laying a foundation to streamline clinical testing and drug development, leaders from the US Food and Drug Administration body (“FDA”) took their Critical Path Initiative (CPI) from concept to implementation.

There remained public concerns about drug safety, dangerous imports, and rising pharmaceutical costs, much like today here in the UK for dementia. But here the UK taxpayer is in effect helping to underwrite drug development costs for these blockbuster revenue companies. Whilst political leaders use the limp mantra ‘you shouldn’t have to choose between cure and care’, in effect the choice has been made. Care is on its knees.

The famous political saying from Carville is of course ‘it’s the economy stupid, but don’t forget about healthcare.’ With the current Government’s growing economy, there is little joy from the people who can deliver potentially high quality professional care – nurses and doctors – who are unanimously demoralised and destroyed by Jeremy Hunt and his colleagues, wherever they may be.

The shambolic state of the English dementia policy could not have been made clearer by the lack of discussion of care pathways and clinical specialist nurses in dementia. What resulted was a underwhelming appalling document known as the ‘Implementation Plan’ for Dementia 2020 from the Department of Health.

The fluffy ‘health MOTs’ for people in their 40s is not evidence based at all. It is the pipedream of a non-clinical policy wonk, wishing to ensnare the ‘worried well’ into the lare of the private insurance industry, as I describe here. Nobody is of course objecting to true professional health promotion, but there are limitations to promoting ‘brain health’ – in the same ways to improve a healthy leg has limitations for you dealing with a dislocated hip or fractured neck of femur.

The relative lack of substantial professional clinical input really shone through in many areas, such as the lack of discussion of co-morbidities. Many of the ideas are gimmicks which have been recycled ad infinitum in various guises. The aim had been to assess ‘the lessons learnt’ from the only ever English dementia strategy, “Living well with dementia”, in 2009, but clearly the Department of Health cannot even been bothered to do that, not wishing perhaps to scrutinise the appalling state of social care or the high number of inappropriate referrals to memory clinic.

Or maybe the Department of Health do not want to discuss why primary care is not well placed to deliver on dementia diagnosis, when that arm of the profession is suffering a recruitment crisis, overwhelmed by bureaucracy and regulation, and is relatively grossly underfunded.

If the rest of English dementia policy were in a fit state, then a Drug Discovery Fund would be something to shout about. But the fact that there were 101 spectacular failures in drug development for dementia between 1998 and 2012 is also a fact.

None of us know what the future will bring. To be prepared is half the victory.

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Ayres Rock Chris Shibley

 

 

Through public awareness initiatives such as “Share the orange” from the Alzheimer’s Research UK charity, slowly more and more people in the general public are cottoning onto the idea that dementia is not a normal part of ageing.

An ignorance of what to expect in dementia can be very distressing. Forewarned is forearmed.

I am generally not in favour of aggressive war analogies in the context of dementia, by, say, when you’re overcoming flu, your immune system does launch an attack on a foreign species. You talk about ‘fighting the flu’. Therefore, you can defeat flu.

The problem with the analogy for dementia, however, is that you rarely hear of people who have won their fight against dementia. Defeating a type of dementia is not an unworthy aim, though.

If you do, however, decide to extend the military metaphor for dementia, then there’s no doubt for me that, as attributed to Miguel de Cervantes, “to be prepared is half the victory”.

About 16 years ago to the day, I started my Ph.D. up in Cambridge. I would visit families with dementia all around East Anglia, and do some specialised psychological assessments of areas such as memory or planning in people living with the then-called ‘frontal variant’ of frontotemporal dementia.

I came to focus on decision-making, and I found that risk taking was a much under-recognised feature of people with a type of dementia known as the behavioural variant of frontotemporal dementia, whose calling sign is quite an insidious change in behaviour and personality. This is highly relevant to personal budgets in social care, and also development of therapeutic targets (taking in work in the related area of impulsivity.)

Now, it is known, not thanks to me but thanks to a handful of specialised laboratories around the world, that your genetic blueprint you’re born with can be traced to various well defined categories of frontotemporal dementia, a type of dementia that affects the frontal and temporal bits of your brain. (They’re the parts of the brain right at the front and near your ear respectively.)

Bring the clock forward to 2016, and we now have quite a good idea of tiny parts of the cell, the basic unit of the human body, called “ribonucleosides” which seem to act funny in some of the frontotemporal dementias. This is, of course, significant as this gives us leverage to attack the dementia process – like looking for the weakest link in the enemy army.

I didn’t go to Cambridge last year. In fact, I had not been to Cambridge for a decade until recently when I was invited to give a talk on risk and dementia at one of the Cambridge Colleges.

I instead went to Australia with Chris Roberts, his wife Jayne Goodrick, and one of their daughters. Chris is presently living with a mixture of vascular dementia and Alzheimer’s dementia. Visiting Ayres Rock was my personal highlight.

Again, it’s the case that very bright researchers have worked out that changes to the blood flow around the brain can somehow lead to a process of dementia. It’s well known vascular changes in the human body can be brought about by a whole host of factors such as diet and smoking – this again gives a means of preventing the rate of progression of an enemy army.

neuroanatomy

[source here].

Knowing the plumbing of the human brain can therefore very relevant to working out how to stop the rate of decline in dementia. How well blood flows in the brain is closely linked to the health of the brain through a process called “neurovascular coupling”.

When you think of the size of the numbers of people around the world living with dementia, close to 50 million, this leaves you with two options. One is to give up altogether; the other is to build up bit by bit a detailed working knowledge of the dementias.

I know Chris, living with dementia to the best of his ability, and in an environment which can be optimised as ‘dementia friendly’ as possible, works relentlessly to campaign for recruitment into research in dementia (“Join Dementia Research”).

Working out how factors in the circulation might be progressing in Chris’ dementia would be a wonderful thing to know, and provide much greater precision for a possible therapy one day for people who have the type of dementia Chris has.

The aim of research into dementias is to gather this detailed knowledge, pool it together and share it, and think about how best it can be used to promote and protect the health of citizens. Research is an investment which is inevitably very costly due to manpower and consumables.

Nonetheless, the next step is to make sure the right mood music (and money) is in place to convert this knowledge into something meaningful for a person living with dementia. The regulatory infrastructure of course around the world needs to be able to responsive and responsible to such innovations.

I wish Chris well as he helps to launch next week’s Research Conference for Alzheimer’s Research UK up in Manchester, where other brilliant initiatives such as ‘Dementia United’ providing devolved joined up health and care services for dementia are also afoot.

Anyone involved in research knows it’s a marathon not a sprint; and most researchers I know know they’re in it for the long haul. But we can only get more detailed knowledge as, in other areas, we have a strong, high capacity, workforce making use of all available specialist talent.

You see, none of us know what the future will bring. Anything can happen to anyone at any time.

The UK, being the sixth richest country in the world, is an unique position to do this. The travesty is that social care is on its knees, and this is a painful truth for many people trying to live with dementia presently. And this needs correcting.

The future, on the other hand, might be brighter, if not necessarily orange.

 

 

 

My day at the Alzheimer’s Research UK Supporters Group at the Wellcome Trust London

Shibley Rahman 1 Comment

“Our vision is a world where people are free from the fear, harm and heartbreak of dementia.”

The history of the society is indeed formidable, described clearly from 1992.

I remember asking the late Prof Richard Doll, eminent physician, how he discovered the link between smoking and lung cancer. He answered with characteristic humility ‘serendipity’, and then quoted a definition of serendipity as ‘looking for a needle in a haystack and finding the farmer’s daughter’.

I think research does involve serendipity.

For example, it has only latterly been recognised that inflammation has quite a big rôle to play in neurodegeneration processes too; and my hunch is that this may one day form a way of approaching dementia pharmacologically.

How certain biological substances form and build up in the brain in dementia continues to be a curiosity. I remember being much inspired by the work of Prof Maria Spillantini at Cambridge, who was always incredibly modest about the advances being made in her laboratory.

I loved my day yesterday at the Wellcome Trust here on Euston Road in London.

Few people have really made an impact on me as when I saw Valerie Blumenthal talking about living with symptoms of a type of dementia called posterior cortical atrophy on BBC Breakfast. I am in fact hugely looking forward to Valerie’s book, which I anticipate will be brilliant.

Possibly it is in fact impossible to draft any strap line of a charity focused on dementia, but the mission statement of the Alzheimer’s Research UK is as good as one might reasonably wish for.

I happen to hold a personal position that research into dementia should be also be of benefit to those 47 million in the world who live with dementia daily. This not only might include treatment for symptoms, maybe memory, but also practical assistive help; or even therapy which might slow the disease process right down.

But it also does very much include active prevention of disease in people who already have developed dementia. I feel that the workstreams in non communicable disease led by WHO have had huge impact here.

Do I feel that there will be a pharmacological offering for dementia? For the whole of dementia, no, but for select different types of dementia, definitely maybe. I think we’ll be one day where cancer is, but this is only possible with parity of funding.

Do I feel it’s fair to blame charities on the woes of dementia policy elsewhere? No. It is up to voters and political parties to make the case for investment in social care, which clearly has been deficient until now. I don’t think it’s possible to make charities such as Alzheimer’s Research UK ultimately responsible for everything in dementia policy.

Do I feel I met some very nice people? Most definitely. I met members of public, ARUK staff and scientists who are extremely good people. Chris Roberts and Jayne Goodrick were there too – like family to me.

I think Hilary Evans leads the charity with remarkable clarity – to a degree that is really quite exceptional even in this crowded field – and had a very clear understanding of the raw societal challenges of dementia. My overall feeling, from doing a day of workshops which were thought provoking and enjoyable in equal measure, was that the charity is definitely in ‘listening mode’ and is in fact using its considerable responsibility to execute extremely good work. The charity is opposite to arrogant in its attitude, and had both a realistic and achievable view of what it hoped to achieve in the next few years.

 

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#WorldAlzheimersDay – who is protecting whom?

Shibley Rahman 0 Comments

Assessing risk is a critical part of English dementia policy at all levels. I again found myself talking about risk as I saw responses to World Alzheimer’s Day which was yesterday on September 22nd 2015.

I don’t especially like the term ‘wandering’ for people with dementia. This term, like ‘challenging behaviours’ has become seemingly legitimised through the hundreds of papers on it in the scientific press, and the grants no doubt equivalent to hundreds of thousands of dollars probably. I think the term, intentionally or not, attributes blame. And as I moot in the tweet below, this is potentially a problem, especially one considers that a dementia charity should not ideally be fundraising out of sheer fear.

Tweet 1

Don’t get me wrong. I think charities have an incredibly important part to play, and they do, in educating people about dementia; and generally ‘raising awareness’ howeverso defined. Take for example this helpful tweet from the Alzheimer’s Disease International containing a relevant infographic about the scale of the dementia epidemiology.

Infographic

I had a hunch that something was very awry about yesterday when my colleague Simon Denegri tweeted something which caught my eye. Let me introduce you to Simon. He’s Chair, INVOLVE, NIHR National Director for Patients and the Public in Research, and, importantly, a nice guy.

The tweet, and the main subject of the research, is pretty self explanatory in fact.

denegi

The point Simon raises is worth thinking about, I feel. Is updating the epidemiology of dementia every year, nay every month, or even every week, an effective way of genuinely raising public awareness – or is it rather a lazy way to campaign on it? Obviously, playing devil’s advocate, one should argue that this main issue should be raised until something happens, but with a cure for dementia a long way distant it seems that this option is not likely.

So how about offering some solution instead? In other words, having scoped the problem, why not offer hope instead of fear through the huge volume of research in improving quality of life for people living with dementia and carers. Here’s the thing: there are 850,000 people living with dementia at the moment currently, and there’s got to be something in it for them with all this coverage.

I call fixating on the ‘tsunami’, ‘time bomb’ or ‘tidal wave’ “the shock doctrine” to make you want to dig into your deep pockets, to make you donate to a dementia charity. BUT  – with social care funding on its knees, having not been ringfenced since 2010 – is this actually a luxurious response to a rather serious immediate problem? Long before #DementiaWords ‘got sexy’, I presented my poster (PO124) on the hyperbolic language used in the G8dementia proceedings, in the Alzheimer Europe 2014 conference.

Here’s the rub.

Jeremy Hughes and the Alzheimer’s Society have been hugely successful with the ‘Dementia Friends’ campaign, which has seen a roll-out of information sessions on the basics of dementia for the whole country. Yesterday was a good opportunity to talk about that.

Dementia Friends

But meanwhile Alzheimer’s Research UK, which indeed does formidable work for the research infrastructure on dementias in the UK, rolled out this in a blogpost yesterday. The phraseology of the remark, “At Alzheimer’s Research UK, our hope is for a different kind of future, one where future generations will be free of this life-shattering condition”, is the opposite to one of the central messages of Dementia Friends, that ‘it is possible to live well with dementia’.

shattering

I don’t, of course, want to downplay the huge significance of the disclosure of the diagnosis of dementia as a life event for all those involved, not least the direct recipient of that diagnosis.

Sadly, we’ve been here before. All of these came to the fore when Richard Taylor PhD, one of the founding members of Dementia Alliance International, (DAI), pleaded, “Stop using stigma to raise money for us”, in the Alzheimer’s Disease Conference in 2014 in Puerto Rico. Actually, the DAI, a group run by people living with dementia, has been working with Alzheimer’s Disease International to make things much better, in no small part at all due to the gigantic efforts of its current Chair Kate Swaffer (@KateSwaffer).

All of this leads to me wonder who exactly is protecting whom? I wouldn’t go so far as to say that the public needs protecting from large dementia charities, but the sway they hold on policy is not inconsiderable; whether this is on the cure v care resource allocation in dementia, or whether there should be specialist nurses as well as dementia advisors (as I argued this year both in the ADI and Alzheimer Europe conferences).

There’s no doubt, as regards safeguarding issues, that people with dementia need to protected from risk where it is proportionate to do so. As I have long argued, you need to embrace risk to live well with dementia. But it is worth thinking about on whose part we are negotiating risk? Damian Murphy’s excellent blogpost yesterday emphasises how we cannot necessarily assume that carers and persons with dementia have the same (or even similar) viewpoints: this is directly relevant, say, on whether a person with dementia with a carer gets a GPS tracking device?  (I duly anticipate and expect Damian’s contribution here, by the way, to be seminal one, by the way.)

A long time ago when I was reading some of the management literature, I was really impressed by a paper to which Prof Michael Porter contributed on strategy and society (co-author Mark Kramer) in the Harvard Business Review.

Mark in a slide once summarised four crucial tenets of observing this re-articulated corporate social responsibility thus.

Kramer

I, for one, would like to see all campaigning done by the dementia charities seen through this prism; and also bearing in mind the clinical, if not societal, question cui bono?